Self-sustaining pathological loops may be involved in epilepsy. Indeed, it is clinically known that the occurrence of a seizure makes it likely that additional seizures will occur in the future. However, the underlying biology is not well understood. This application proposes to study specific mechanisms of network signaling that may be involved in a self-sustaining loop underlying some forms of intractable epilepsy. Our working hypothesis is based on the fact that seizures often damage the brain regions involved, such as the hippocampus, and induce reactive changes and proliferation of astrocytes and microglia. Both cell types are a rich source of the chemokine stromal cell-derived factor 1 (SDF-1), whose CXCR4 receptors are abundantly expressed by hippocampal Cajal-Retzius cells. We will study the synaptic interactions between Cajal-Retzius cells and GABAergic interneurons, and how their network dynamics are affected by SDF-1. Our preliminary data suggest the possibility that SDF-1-mediated activation of Cajal-Retzius cells is the trigger of epileptiform activity in GABAergic networks. Epileptiform synchronization of GABAergic interneurons in some patients unresponsive to pharmacological treatment is believed to generate excitatory GABAA receptor-mediated signaling, which may lead to interictal-ictal transitions and promote seizures. Thus, new seizures would be produced, and additional reactive gliosis would maintain or even increase the available levels of SDF-1, restarting the pathological loop. Defining the molecular and cellular details of a putative circuit initiating/maintaining epileptiform activity in GABAergic networks is important to provide new insights for the development of different therapeutic strategies for the prevention and/or control of some forms of intractable epilepsies. We plan to use a combination of in vitro electrophysiology and anatomy applied to slices obtained from genetically-engineered animals (CXCR4-EGFP transgenic mice). PUBLIC HEALTH RELEVANCE: The purpose of this application is to identify novel neuronal mechanisms that contribute to epileptogenesis in a specific microcircuit of the hippocampus, which is a brain region with a low threshold for seizures. In more detail, this proposal concerns epileptiform activity in vitro that is sustained by excitatory GABAergic input and is similar to dynamic patterns occurring in some epileptic patients who do not respond to conventional therapies. These epileptic patients require surgical removal of the epileptic focus: hence understanding the cellular details underlying their illness is imperative to provide new strategies for medical treatments. .